Slc7a11, also commonly known as xCT, is the functional component of system Xc-. It functions as a cystine/glutamate antiporter, importing extracellular cystine in exchange for intracellular glutamate release at a 1:1 ratio. This process is crucial for glutathione biosynthesis and antioxidant defense, and thus plays a significant role in regulating cellular redox homeostasis, ferroptosis, and drug resistance in cancer [1,3].

In hepatocellular carcinoma (HCC), hepatocyte-specific ablation of the stress-responsive transcription factor ATF4 increased susceptibility to ferroptosis and accelerated HCC development due to decreased expression of Slc7a11. Ectopic expression of Slc7a11 in ATF4-deficient primary hepatocytes and mouse livers reversed ferroptosis susceptibility and hepatocarcinogenesis, suggesting that ATF4 inhibits ferroptosis-dependent inflammatory cell death through maintaining Slc7a11-mediated glutathione production [2].

In liver fibrosis, sorafenib triggered hepatic stellate cell (HSC) ferroptosis via inactivating the HIF-1α/Slc7a11 pathway, which attenuated liver injury and fibrosis [4].

In breast cancer, metformin induced ferroptosis by inhibiting the UFMylation of Slc7a11, reducing its protein stability and suppressing tumor growth [5].

In non-alcoholic fatty liver disease (NAFLD), arbutin alleviated fatty liver by inhibiting ferroptosis via the FTO/Slc7a11 pathway [6].

In conclusion, Slc7a11 is essential for maintaining cellular redox balance through cystine import for glutathione synthesis. Its role in diseases such as HCC, liver fibrosis, breast cancer, and NAFLD has been revealed through in vivo studies, especially with gene-knockout or related models. These studies on Slc7a11 provide insights into disease mechanisms and potential therapeutic targets for these conditions.